DESCRIPTION: The lungs must accept the entire cardiac output. Despite large variation in total pulmonary blood flow, intrapulmonary distribution of flow is regulated on a second to second basis by local mechanism. Thus, optimal matching of blood flow with ventilated alveoli is maintained by the selective increase in the resistance of vessels traversing alveoli with reduced oxygen tension (hypoxic pulmonary vasoconstriction, HPV). Intrapulmonary blood flow is, as a consequence, diverted away from those alveoli not being well ventilated to those with an adequate partial pressure of oxygen. Endogenous vasodilators have been suggested to modulate vasoconstriction within the lungs preventing, thereby, excessive increases in pulmonary vascular pressures. Under some conditions, however, this vasodilation opposes those mechanisms (HPV) required for the maintenance of optimal ventilation- perfusion relationships. When matching of ventilation with perfusion is impaired, e.g., in acute lung injury (ALI), venous admixture increases resulting in systemic arterial hypoxemia. A long-term objective of this laboratory has been, and is, to define the role of humoral agents, specifically products of arachidonic acid (AA) metabolism, in the regulation of the pulmonary circulation under physiological as well as pathophysiological conditions. The impetus for the present proposal was the observation that in several animal models of ALI, inhibition of cyclooxygenase (COX) activity prevented the increase in venous admixture. It was suggested that a COX-mediated vasodilator product of AA metabolism, most likely prostaglandin (PG) I2, was responsible for the increase in venous admixture in ALI. However, the evidence was meager that PGI2 participated in the pathophysiological mechanism of increased venous admixture in ALI. Several products of cytochrome P-450 were observed to require COX activity to express vasodilator properties. Further, inhibition of cytochrome P-450 prevented the increased venous admixture associated with ALI. Cytochrome P-450 monooxygenase products of AA metabolism were then proposed to be fundamental participants in the control of the pulmonary circulation. To address this hypothesis in the present proposal, chemical, biochemical and pharmacological approaches will be used at the tissue, organ and whole animal (dog) levels. Three Specific aims have been developed: 1) to identify the products of cytochrome P-450 monooxygenase-mediated AA metabolism synthesized by the lung; 2) to define, pharmacologically, the vasoactivity of those products identified under Specific Aim one in the intact pulmonary circulation and in isolated pulmonary vascular rings; and, 3) to determine the mechanism(s) by which cytochrome P-450 products of AA metabolism affect vascular tone in the pulmonary circulation. Identification of a previously unappreciated endogenous regulator of pulmonary blood flow will advance one's understanding of the multiple mechanism which regulate the intrapulmonary distribution of blood flow and might permit more rational therapeutic approaches to clinical conditions associated with impaired ventilation-perfusion relationships.